Document Detail


The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice.
MedLine Citation:
PMID:  21926192     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AG014699 was the first inhibitor of the DNA repair enzyme PARP-1 to enter clinical trial in cancer patients. In addition to enhancing the cytotoxic effect of DNA-damaging chemotherapies, we have previously shown that AG014699 is vasoactive, thereby having the potential to improve drug biodistribution. The effectiveness of the clinical agent doxorubicin is confounded both by poor tumor penetration and cardiotoxicity elicited via PARP hyperactivation. In this study, we analyzed the impact of AG014699 on doxorubicin tolerance and response in breast (MDA-MB-231) and colorectal (SW620, LoVo) tumor models in vitro and in vivo. As anticipated, AG014699 did not potentiate the response to doxorubicin in vitro. In vivo, AG014699 did not influence the pharmacokinetics of doxorubicin; however, it did ameliorate cardiotoxicity. Both toxicity and extent of amelioration were more pronounced in male than in female mice. AG014699 improved vessel perfusion in both MDA-MB-231 and SW620 tumors; however, this neither led to improved tumor-accumulation of doxorubicin nor enhanced therapeutic response. In contrast, when combined with radiotherapy, AG014699 significantly enhanced response both in vitro and in vivo. Real-time assessment of tumor vessel function and companion histologic studies indicate that doxorubicin causes a profound antivascular effect that counters the positive effect of AG014699 on perfusion. These data indicate that although AG014699 can enhance response to some chemotherapeutic drugs via improved delivery, this does not apply to doxorubicin. PARP inhibitors may still be of use to counter doxorubicin toxicity, and if the gender effect translates from rodents to humans, this would have greater effect in males.
Authors:
Majid Ali; Marzieh Kamjoo; Huw D Thomas; Suzanne Kyle; Ivanda Pavlovska; Muhammed Babur; Brian A Telfer; Nicola J Curtin; Kaye J Williams
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-09-16
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  10     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-14     Completed Date:  2012-05-11     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2320-9     Citation Subset:  IM    
Affiliation:
School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Manchester, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Combined Chemotherapy Protocols / adverse effects,  pharmacology,  therapeutic use*
Cardiotoxins / antagonists & inhibitors
Cell Line, Tumor
Cytoprotection / drug effects
Doxorubicin / administration & dosage*,  adverse effects*,  antagonists & inhibitors
Drug Synergism
Female
Heart / drug effects
Humans
Indoles / administration & dosage*,  pharmacology
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Models, Biological
Neoplasms / blood supply,  drug therapy*,  metabolism,  radiotherapy*
Perfusion
Poly(ADP-ribose) Polymerases / antagonists & inhibitors
Radiation Tolerance / drug effects*
Treatment Outcome
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
A8200//Cancer Research UK; C7820/A8200//Cancer Research UK
Chemical
Reg. No./Substance:
0/AG 014699; 0/Cardiotoxins; 0/Indoles; 23214-92-8/Doxorubicin; EC 2.4.2.30/Poly(ADP-ribose) Polymerases
Comments/Corrections

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